Behavior is affected by genetics, the environment, and a complex interplay between the two. Exposure to nutritional deficiencies at critical time points during development, particularly while in utero and during the postpartum period, increases the risk of psychiatric disease in humans, and alters behavioral outcomes in animal models of human psychiatric disease. Some of these effects have been linked to changes in methylation and gene expression, implying that epigenetic factors may contribute to the underlying disease process. Identifying specific genes that respond both to environmental variation and that influence behavior in animal models can reveal not only genetic pathways involved in brain development and function, but also how such pathways are sensitive to external factors in the environment. Such studies can thereby shed light on the etiology of human psychiatric disease, and provide new clues to prevention and treatment. The goal of this proposal is to identify genes whose actions are modulated by maternal nutrition and that influence behavior in adult offspring. The experimental design contains several innovative components, and makes use of a powerful new genetic resource for mouse studies, the Collaborative Cross (CC). The CC is a panel of recombinant inbred mouse lines, each of whose genomes comprises a balanced but randomized mosaic of genetic material from eight diverse founder strains. The proposed study uses the known haplotypic composition of the CC lines to generate sparse diallel cross of reciprocal matings between CC strains (CC recombinant inbred mice, or CC-RIX) that allows a genomewide survey of genetic effects that vary by parent of origin and maternal diet. Specifically, mating CC females will be exposed to nutritional deficiencies during gestation and in the postpartum period. CC-RIX offspring will then be subject to behavioral testing and assayed for gene expression by microarray. Novel statistical methodology developed during the project will be applied in order to identify and characterize strain- and diet-specific effects, as well as parent of origin effects due to allelic imbalance. Candidate genes will be assessed by direct behavioral examination of knockout mice and also by knockout complementation testing to validate the role of both diet and strain. The proposed research represents a novel application of a powerful new genetic platform in order to elucidate how genetics, in utero exposures, maternal diet and parent-of-origin combine to affect behavior.